Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge

HIV infection is accompanied by an early immune dysfunction limiting host c ontrol of virus and likely contributing to difficulties in achieving a succ essful vaccine against HIV. We report here that the HIV Tat protein is stro ngly immunosuppressive, both immediately after immunization of mice with so luble protein (sTat), and in seroconverting humans, and propose that Tat-in duced suppression cripples immune surveillance to HIV infection. We show th at macrophages are sensitive to sTat stimulation at concentrations 1,000-fo ld lower (500 pM) than T cells, and this stimulation is accompanied by the immunosuppressive induction of Fas ligand on the macrophage. T cell prolife rative defects induced by sTat in vitro can be completely (at lower concent rations of sTat) or partially (at higher concentrations) reversed by antago nists to Fas/Fas ligand interaction. We further report a method to preserve immunogenicity while inactivating Tat immunosuppression through oxidation, which advances the use of oxidized Tat as a component of an anti-HIV vacci ne. These observations define additional methods to study the immunosuppres sive functions of sTat that now may be rapidly applied to primary isolates from individuals with differing clinical courses. Our Endings have immediat e relevance for vaccine development, by describing and supporting a strateg y that includes inactivated sTat in a multicomponent, anti-HIV vaccine.